Collagen Mimetic Peptides

bioengineering Review Collagen Mimetic Peptides Yujia Xu * and Michele Kirchner Department of Chemistry, Hunter College of the City University of New York, 695 Park Ave., New York, NY 10065, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-(212)-772-4310 Abstract: Since their first synthesis in the late 1960s, collagen mimetic peptides (CMPs) have been used as a molecular tool to study collagen, and as an approach to develop novel collagen mimetic biomaterials. Collagen, a major extracellular matrix (ECM) protein, plays vital roles in many physio- logical and pathogenic processes. Applications of CMPs have advanced our understanding of the structure and molecular properties of a collagen triple helix—the building block of collagen—and the interactions of collagen with important molecular ligands. The accumulating knowledge is also paving the way for developing novel CMPs for biomedical applications. Indeed, for the past 50 years, CMP research has been a fast-growing, far-reaching interdisciplinary field. The major development and achievement of CMPs were documented in a few detailed reviews around 2010. Here, we provided a brief overview of what we have learned about CMPs—their potential and their limitations. We focused on more recent developments in producing heterotrimeric CMPs, and CMPs that can form collagen-like higher order molecular assemblies. We also expanded the traditional view of CMPs to include larger designed peptides produced using recombinant systems. Studies using recombinant peptides have provided new insights on collagens and promoted progress in the development of collagen mimetic fibrillar self-assemblies. Keywords: collagen mimetic peptides; fibril-forming collagen peptide; homotrimer triple helix; heterotrimeric triple helix; recombinant collagen peptides; design of collagen mimetic peptides; collagen receptors; collagen-based biomaterials; extracellular matrix; synthetic collagen Citation: Xu, Y.; Kirchner, M. Collagen Mimetic Peptides. Bioengineering 2021, 8, 5. 1. Introduction https://doi.org/10.3390/ The term collagen mimetic often conjures up two different ideas: Those that intend bioengineering8010005 to capture the biological functions of collagen by mimicking the structural hierarchy of Received: 23 November 2020 collagen building up from the triple helix, and those “inspired” by the properties of collagen Accepted: 31 December 2020 and trying to mimic its nano-scale structure and function using non-biological polymers. Published: 5 January 2021 Examples of the latter include the molecular scaffold made of electrospun polymers with a similar diameter and morphology as collagen fibrils, or nano-scale tubes self-assembled Publisher’s Note: MDPI stays neu- from non-peptide building blocks but decorated with certain amino acid residues on tral with regard to jurisdictional clai- the surface mimicking the functions of collagen [1–5]. Applications of collagen mimetic ms in published maps and institutio- peptides (CMPs) belong to the former. Peptides are developed to resemble collagens in nal affiliations. their amino acid sequence, in their structure, and in their bioactivity. The principle of such an approach falls within the general premise of structural biology that at the foundation of the biological functions of a biomolecule is its molecular structure. Copyright: © 2021 by the authors. Li- 1.1. The Macromolecular Assembly of Collagen censee MDPI, Basel, Switzerland. Collagen is a family of extracellular matrix proteins with considerable diversity both This article is an open access article in structure and in function. A total of 28 different types of collagen have been identified distributed under the terms and con- ditions of the Creative Commons At- in this super family, among which the fibrillar collagens are the most abundant and are tribution (CC BY) license (https:// also the best characterized [6–8]. The major fibrillar collagens include collagen types I, II, creativecommons.org/licenses/by/ and III. Collagen type I is the major collagen in bones, skin, and tendon. Collagen type II 4.0/). presents primarily in cartilage. Type III collagen often coexists with type I in skin, and in Bioengineering 2021, 8, 5. https://doi.org/10.3390/bioengineering8010005 https://www.mdpi.com/journal/bioengineering Bioengineering 2021, 8, 5 2 of 24 blood vessel walls. Other types of fibrillar collagens are present at a lower amount and are often found coexisting with the three major types. The structural hierarchy of all collagens starts from the building block: The collagen triple helix [8,9]. A collagen triple helix consists of three polypeptide chains (often referred to as the α chains) coming together in parallel with a precise one residue staggering at the ends [9,10]. The three chains tightly wrap around each other about a common axis in a right-handed helical twist to form a rod-like helical conformation (Figure1A). The tight packing of the triple helix requires a Gly residue at every third position, giving rise to the characteristic (Gly-X-Y)n repeating sequence. The obligatory Gly residues are buried at the center of the helix, the side chains of X and Y residues are largely exposed to solvent. The triple helix is often considered a “linear molecule” because of its uniform backbone conformation characterized by an ~0.86 nm helical rise per Gly-X-Y tripeptide [11–14]. The side chains of the X and Y residues can be described as a linear sequential array in an N-to-C directionality spiraling around the surface of the molecule (Figure1A). Figure 1. The rod-shaped conformation of the triple helix. (A) The structure of the homotrimer triple helix T73–785 [15] was generated using DeepView–Swiss-PdbViewer (PDB: 1bkv). The helix is shown with the N-terminus on top; the Thr residues are shown in green, Arg in blue, hydrophobic residues in dark gray. (B) In order to show the asymmetric structure of a heterotrimer associated with different chain registers, a type I collagen like the AAB heterotrimer model was created using DeepView by replacing the Thr of one of the three chains of 1bkv to Ala (side chain shown in black). The amino acid residues included in this heterotrimer model are ITGARGLAG for the two identical strands, and IAGARGLAG for the third, mutated strand. The three structures are shown in the identical view of the backbone, with the N-terminus on top. The three polypeptide chains of a triple helix can be identical in the form of a homotrimer, or they can be different in amino acid sequences forming a heterotrimeric triple helix [8]. Collagen type II and collagen type III are homotrimers, while collagen type I is a heterotrimer consisting of two identical α1 chains, and one α2 chain. There is about 72% sequence similarity between the two α chains in the triple helix domain of type I collagen. Because of the one residue stagger between the adjacent strands in the triple helix, the analogous residues in each strand are unique even in a homotrimer environment (Figure1A) [10,16–18]. The three strands are usually called leading, middle, and trailing, as viewed from their N-termini. The chain-stagger-related asymmetry in structure is par- ticularly pronounced in a heterotrimer (Figure1B). Thus, for type I collagen the surface features of the triple helix can be very different depending on which chain is in the leading, middle, or trailing position. There are three possible chain registers for type I collagen: α1α1α2, α1α2α1, and α2α1α1, which are often referred to as α2 trailing, α2 middle, and α2 leading, respectively. Unfortunately, determining the chain register is not at all easy. The correct chain register of type I was accepted to be α1α2α1 [19,20]. Emerging data Bioengineering 2021, 8, 5 3 of 24 from studies using CMPs, however, are challenging this chain alignment in favor of an α1α1α2 register with the α2 chain in the trailing position (details below) [21]. Inside the cell, the C-terminal globular domain, the C-propeptide, was believed to be responsible for both chain selection and chain registration [22]. Structural studies of type I collagen C-propeptide have provided a mechanism for heterotrimerization of the C-propeptide. How the structure of the C-propeptide determines the chain alignment of the triple helix domain, however, remains a mystery [23,24]. Collagens in tissues are higher order, supramolecular assemblies of triple helices. Fibrillar collagens self-associate laterally with a specific 67 nm staggering at the ends to form fibrils (Figure2A,C) [ 25–30]. Fibrillar collagens are large molecules consisting of more than 1000 residues per single polypeptide chain in uninterrupted (Gly-X-Y) repeating sequences, forming a long triple helix about 300 nm long and ~1.5 nm in diameter. Each triple helix compromises about 4.4 × 67 nm in its total length. The staggered arrangement would thus generate long, smooth fibrils with alternating gap-and-overlap regions every 67 nm. This 67-nm structure is termed a D-period, which consists of a 0.4D overlap zone and a 0.6D gap region. The overlap and the gap zones appear as light and dark bands, respectively, when examined using an electron microscope, giving rise to the characteristic striation appearance of collagen fibrils (Figure2A). In the fibrils, the triple helix further adopts a right-handed super-twist around the microfibrils [31–35]. Because of this super- twist, there is an uneven exposure of different parts of the triple helix on the fibril surface (Figure2B); as to which specific sections of the triple helix might be exposed on the surface of the fibrils is still under debate [32,36,37]. Figure 2. The structural hierarchy of fibrillar collagen. (A) Electron micrograph of collagen fibrils showing the characteristic striation pattern of the D-period and the tipped ends. (B) The unit cell of collagen fibril showing the staggered and intertwined arrangement of five triple helices (in different colors) due to the super-twist of the triple helices in fibrils [33].

Load more